Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000213270 | SCV000273907 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-04-11 | criteria provided, single submitter | clinical testing | The c.202_203delGCinsTT variant (also known as p.A68L) is located in coding exon 2 of the CDKN2A gene and results from an in-frame deletion of GC and insertion of TT between nucleotide positions 202 and 203. The alanine at codon 68 is replaced by leucine. This variant has been previously reported in several kindreds with malignant melanoma (Pastorino L et al, Pigment Cell Melanoma Res 2008 Dec; 21(6):700-9; Cust AE et al, J. Med. Genet. 2011 Apr; 48(4):266-72; Maubec E et al. J Am Acad Dermatol 2012 Dec;67(6):1257-64; Bruno W et al. J Am Acad Dermatol 2016 Feb;74(2):325-32; De Simone P et al. Int J Mol Sci, 2020 Dec;21). In one family, the alteration was found to segregate with disease in four individuals (Soufir N et al, Hum. Mol. Genet. 1998 Feb; 7(2):209-16). This variant was also detected in 1/422 Italian pancreatic cancer patients (Puccini A et al. Cancers (Basel), 2022 Sep;14). In addition, functional studies of A68L mutants have demonstrated decreased binding affinity to CDK4, irregular nuclear localization, and reduced mediation of cell-cycle arrest compared to wild type (Rizos H et al, J. Biol. Chem. 2001 Nov; 276(44):41424-34; McKenzie HA et al. Hum Mutat 2010 Jun;31(6):692-701; Miller PJ et al, Hum. Mutat. 2011 Aug; 32(8):900-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000472170 | SCV000545527 | likely pathogenic | Familial melanoma | 2024-03-09 | criteria provided, single submitter | clinical testing | The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 68 of the CDKN2A (p16INK4a) protein (p.Ala68Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with cutaneous melanoma, pancreatic cancer and/or renal cancer (PMID: 9425228, 18983535, 25780468, 30274933, 30291219, 32782288, 36139606). It has also been observed to segregate with disease in related individuals. This variant is also known as c.245_246delinsTT (p.Arg82Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 230375). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 11518711, 19260062, 20340136, 21462282). This variant disrupts the p.Ala68 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been observed in individuals with CDKN2A (p16INK4a)-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic. In the absence of additional clinical evidence, this variant has been classified as Likely Pathogenic. While this evidence indicates that the variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, the association of this variant with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. |
| Myriad Genetics, |
RCV003316206 | SCV004020162 | likely pathogenic | Melanoma-pancreatic cancer syndrome | 2023-03-08 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 20340136, 11518711]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9425228, 26775776, 25780468]. |